EP1994032A1 - Derives pyrazole utilises en tant qu'inhibiteurs du recepteur sigma - Google Patents

Derives pyrazole utilises en tant qu'inhibiteurs du recepteur sigma

Info

Publication number
EP1994032A1
EP1994032A1 EP07711754A EP07711754A EP1994032A1 EP 1994032 A1 EP1994032 A1 EP 1994032A1 EP 07711754 A EP07711754 A EP 07711754A EP 07711754 A EP07711754 A EP 07711754A EP 1994032 A1 EP1994032 A1 EP 1994032A1
Authority
EP
European Patent Office
Prior art keywords
substituted
unsubstituted
chr
optionally
het
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07711754A
Other languages
German (de)
English (en)
Inventor
Rosa Cuberes-Altisent
Joerg Holenz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Esteve Pharmaceuticals SA
Original Assignee
Laboratorios del Dr Esteve SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP06004080A external-priority patent/EP1829875A1/fr
Application filed by Laboratorios del Dr Esteve SA filed Critical Laboratorios del Dr Esteve SA
Priority to EP07711754A priority Critical patent/EP1994032A1/fr
Publication of EP1994032A1 publication Critical patent/EP1994032A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds having pharmacological activity towards the sigma ( ⁇ ) receptor, and more particularly to some pyrazole derivatives, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy and prophylaxis, in particular for the treatment of psychosis.
  • sigma receptor a cell surface receptor of the central nervous system (CNS) which may be related to the dysphoric, hallucinogenic and cardiac stimulant effects of opioids.
  • CNS central nervous system
  • sigma receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J.M. et al, Pharmacological Reviews, 1990, 42, 355).
  • the sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs.
  • SKF 10047 has nanomolar affinity for the sigma 1 ( ⁇ -1) site, and has micromolar affinity for the sigma ( ⁇ -2) site.
  • Haloperidol has similar affinities for both subtypes.
  • Endogenous sigma ligands are not known, although progesterone has been suggested to be one of them.
  • Possible sigma-site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition (Quirion, R. et al. Trends Pharmacol. Sci., 1992, 13:85-86).
  • sigma binding sites are plasmalemmal elements of the signal transduction cascade. Drugs reported to be selective sigma ligands have been evaluated as antipsychotics (Hanner, M. et al. Proc. Natl. Acad. Sci., 1996, 93:8072-8077). The existence of sigma receptors in the CNS, immune and endocrine systems have suggested a likelihood that it may serve as link between the three systems.
  • European patent application EP 0 414 289 Al generically discloses a class of l,2,3,4-tetrahydro-spiro[naphthalene-l,4'-piperidine] and l,4-dihydro-spiro[naphthalene-
  • hydrocarbon as defined in said patent, covers all possible straight chained, cyclic, heterocyclic, etc. groups. However, only compounds having benzyl, phenethyl, cycloalkylmethyl, furyl- or thienylmethyl or lower alkyl or alkenyl as the hydrocarbon substituent at the piperidine nitrogen atom are specifically disclosed. The compounds are stated to displace tritiated di-tolyl guanidine (DTG) from sigma sites with potencies better than 200 nM. 1 -benzyl-
  • 1,2,3,4-tetrahydro-spiro is mentioned as a particularly preferred compound.
  • European patent application EP 0 445 974 A2 generically describes the corresponding spiro[indane-l,4'-piperidine] and spiro[benzocycloheptene-5,4'- piperidine] derivatives. Again the compounds are only stated to displace tritiated di- tolyl guanidine (DTG) from sigma sites with potencies better than 200 nM.
  • DTG di- tolyl guanidine
  • European patent Application EPO 431 943 A relates to a further extremely broad class of spiropiperidine compounds substituted at the piperidine N-atom and claimed to be useful as antiarrhythmics and for impaired cardiac pump function.
  • the said application exemplifies several compounds, the majority of which contain an oxo and/or a sulfonylamino substituent in the spiro cyclic ring system. Of the remainder compounds, the main part has another polar substituent attached to the spiro nucleus and/or they have some polar substituents in the substituent on the piperidine N-atom. No suggestion or indication of effect of the compounds on the sigma receptor is given.
  • Patent applications EP 518 805 A and WO 02/102387 describe sigma receptor ligands having piperidine or spiropiperidine structures.
  • Patent US 4,337,263 discloses l-aryl-4-arylsulphonyl-3-amino propoxy-lH- pyrazoles, wherein the amino group can be constituted by an N-cycle group as morpholine, piperidine or pyrrolidine group. They are used as hypolipemiant or hypocholesteroleminant agents.
  • Patent FR 2301250 describes similar compounds as those mentioned above, such as l,4-diaryl-3-aminoalcoxy pyrazoles, wherein the amino group comprises pyrrolidine, piperidine, hydroxypiperidine, morpholine or piperazine derivatives.
  • Patent Application US2003/0144309 refers to pyrazoles with their 3 position substituted by a dimethylaminoethoxy group and present in their 4 position a pirimidine group. They are used as inhibitors of JNK3, Lck or Src kinase activity.
  • International patent Application WO 02/092573 describes substituted pirazole compounds as inhibitors of SRC and other protein kinases.
  • the compounds present a pyrazol group which are characterized by the substitution at position 3 by an alkoxy group directly bounded to a nitrogen .
  • the invention is directed to a compound of the formula I:
  • R 2 is selected from the group formed by hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR 8 , -
  • Y is selected from substituted or unsubstituted phenyl or naphtyl; substituted or unsubstituted, branched or linear Ci -6 -alkyl; substituted or unsubstituted C 3-8 - cycloalkyl; substituted or unsubstituted heterocyclyl;
  • X is selected from:
  • R ⁇ represent a hydrogen atom; an optionally substituted C M alkyl group; an optionally substituted aryl group; an optionally substituted heteroaryl group; a Ci -4 alkoxy group; a benzyl group; a phenethyl group; or form, together with their bridging nitrogen atom, an optionally substituted heteroaryl group which is optionally condensed to other, optionally at least one heteroatom containing mono- or polycyclic ring system which is optionally at least mono-substituted;
  • X is selected from: -CH 2 -CH 2 -CH 2 -NR x -,
  • R 10 and R 11 independently represent a hydrogen atom; a saturated or unsaturated, optionally at least mono-substituted C 1-6 alkyl group; an optionally at least mono-substituted aryl group; an optionally at least mono-substituted heteroaryl group; an optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloalkyl group; a saturated or unsaturated, optionally at least mono-substituted C 1-6 alkyl-aryl group; a saturated or unsaturated, optionally at least mono-substituted C 1-6 alkyl- heteroaryl group; a saturated or unsaturated, optionally at least mono-substituted C 1-6 alkyl-cycloalkyl group wherein the cycloalkyl group contains optionally at least one heteroatom as ring member;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; t is 1,2 or 3;
  • Re and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, , or halogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • X is selected from:
  • Rs and R $ represent a hydrogen atom; an optionally substituted Ci -4 alkyl group; an optionally substituted aryl group; an optionally substituted heteroaryl group; a Ci -4 alkoxy group; a benzyl group; a phenethyl group; or form, together with their bridging nitrogen atom, an optionally substituted heteroaryl group which is optionally condensed to other, optionally at least one heteroatom containing mono- or polycyclic ring system which is optionally at least mono-substituted;
  • X is selected from:
  • R 10 and R 11 independently represent a hydrogen atom; a saturated or unsaturated, optionally at least mono-substituted Ci -6 alkyl group; an optionally at least mono-substituted aryl group; an optionally at least mono-substituted heteroaryl group; an optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloalkyl group; a saturated or unsaturated, optionally at least mono-substituted Ci -6 alkyl-aryl group; a saturated or unsaturated, optionally at least mono-substituted C 1-6 alkyl- heteroaryl group; a saturated or unsaturated, optionally at least mono-substituted C 1-6 alkyl-cycloalkyl group wherein the cycloalkyl group contains optionally at least one heteroatom as ring member;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; t is 1,2 or 3;
  • Rg and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or halogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • Another preferred embodiment of Group A according to the invention is a compound of the formula I:
  • Y is selected from substituted or unsubstituted phenyl or naphtyl; substituted or unsubstituted, branched or linear C 1-6 -alkyl; substituted or unsubstituted C 3-8 - cycloalkyl; substituted or unsubstituted heterocyclyl;
  • X is selected from:
  • Rs and R$ represent a hydrogen atom; an optionally substituted Ci -4 alkyl group; an optionally substituted aryl group; an optionally substituted heteroaryl group; a C 1-4 alkoxy group; a benzyl group; a phenethyl group; or form, together with their bridging nitrogen atom, an optionally substituted heteroaryl group which is optionally condensed to other, optionally at least one heteroatom containing mono- or polycyclic ring system which is optionally at least mono-substituted;
  • n is selected from 1 , 2, 3, 4, 5, 6, 7 or 8; t is 1,2 or 3;
  • Rg and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, , or halogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • X is selected from:
  • -CHR x - being with Rs and R O , identical or different, represent a hydrogen atom; an optionally substituted C ⁇ alkyl group; an optionally substituted aryl group; an optionally substituted heteroaryl group; a Ci -4 alkoxy group; a benzyl group; a phenethyl group; or form, together with their bridging nitrogen atom, an optionally substituted heteroaryl group which is optionally condensed to other, optionally at least one heteroatom containing mono- or polycyclic ring system which is optionally at least mono-substituted;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; t is 1,2 or 3;
  • Re and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or halogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • Y is selected from substituted or unsubstituted phenyl or naphtyl; substituted or unsubstituted, branched or linear C 1-6 -alkyl; substituted or unsubstituted C 3-8 - cycloalkyl; substituted or unsubstituted heterocyclyl;
  • X is selected from:
  • R 10 and R 11 independently represent a hydrogen atom; a saturated or unsaturated, optionally at least mono-substituted Ci -6 alkyl group; an optionally at least mono-substituted aryl group; an optionally at least mono-substituted heteroaryl group; an optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloalkyl group; a saturated or unsaturated, optionally at least mono-substituted C 1-6 alkyl-aryl group; a saturated or unsaturated, optionally at least mono-substituted Ci -6 alkyl- heteroaryl group; a saturated or unsaturated, optionally at least mono-substituted Ci -6 alkyl-cycloalkyl group wherein the cycloalkyl group contains optionally at least one heteroatom as ring member;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; t is 1,2 or 3;
  • Rg and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, , or halogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • X is selected from:
  • R and R 11 independently represent a hydrogen atom; a saturated or unsaturated, optionally at least mono-substituted Ci -6 alkyl group; an optionally at least mono-substituted aryl group; an optionally at least mono-substituted heteroaryl group; an optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloalkyl group; a saturated or unsaturated, optionally at least mono-substituted C 1-6 alkyl-aryl group; a saturated or unsaturated, optionally at least mono-substituted Ci -6 alkyl- heteroaryl group; a saturated or unsaturated, optionally at least mono-substituted Ci -6 alkyl-cycloalkyl group wherein the cycloalkyl group contains optionally at least one heteroatom as ring member;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; t is 1,2 or 3;
  • Rg and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or halogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • Ri of formulas I or IB is selected from H, halogen, -COR 8 , or substituted or unsubstituted alkyl, preferably it is selected from H, Cl, methyl or acetyl.
  • R 1 of formulas I or IB is hydrogen.
  • R 2 of formulas I or IB is H, aryl, C(O)OR 8 or alkyl, preferably methyl, iso-propyl, phenyl, C(O)O-C 2 H 5 or H.
  • R 3 and R 4 of formula IB are situated in the meta and para positions of the phenyl group.
  • R 3 and R 4 of formula IB are independently selected from halogen, hydrogen, alkoxy, or substituted or unsubstituted alkyl, more preferably selected from hydrogen, halogen, Cl, methoxy or haloalkyl.
  • R 3 and R 4 of formula IB together form a fused ring system, especially a fused ring system leading with the phenyl to form a naphthyl-radical.
  • n of formula I or IB is selected from 2, 3, 4.
  • R 5 and R 6 of formula I or IB are selected from hydrogen or alkyl
  • an optionally substituted heteroaryl group which is optionally condensed to other, optionally at least one heteroatom containing mono- or polycyclic ring system which is optionally at least mono- substituted, especially an indazole or an lH-indazole.
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or another corresponding salt thereof, or a corresponding solvate thereof.
  • R 10 and R 11 of formulas I or IB are independently selected from hydrogen or alkyl.
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or another corresponding salt thereof, or a corresponding solvate thereof.
  • Another aspect the invention is directed to a process for the preparation of a compound of formula (I) or a salt, isomer or solvate thereof.
  • the invention is directed to a pharmaceutical composition which comprises a compound as above defined or a pharmaceutically acceptable salt, enantiomer, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the invention is directed to the use of a compound of formula I or IB for the treatment or prophylaxis of a sigma receptor mediated disease or condition.
  • the compounds as above defined are used in the manufacture of a medicament for the treatment of diarrhoea, lipoprotein disorders, metabolic syndrome, treatment of elevated triglyceride levels, chylomicronemia, hyperlipoproteinemia; hyperlipidemia, especially mixed hyperlipidemia; hypercholesterolemia, dysbetalipoproteinemia, hypertriglyceridemia including both the sporadic and familial disorder (inherited hypertriglyceridemia), migraine, obesity, arthritis, hypertension, arrhythmia, ulcer, learning, memory and attention deficits, cognition disorders, neurodegenerative diseases, demyelinating diseases, addiction to drugs and chemical substances including cocaine, amphetamine, ethanol and nicotine, tardive diskinesia, ischemic stroke, epilepsy, stroke, depression, stress, psychotic condition, schizophrenia; inflammation, autoimmune diseases or cancer; disorders of food ingestion, the regulation of appetite, for the reduction, increase or maintenance of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia,
  • the medicament is for the treatment of pain, especially neuropathic pain, inflammatory pain or other pain conditions, allodynia and/or hyperalgesia, especially mechanical allodynia.
  • the typical compounds of this invention effectively and selectively inhibit the sigma receptor.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no saturation, having one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n- propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc.
  • Alkyl radicals may be optionally substituted by one or more substituents such as a aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio, etc. If substituted by aryl we have an "Aralkyl” radical, such as benzyl and phenethyl.
  • Alkenyl refers to an alkyl radical having at least 2 C atoms and having one or more unsaturated bonds.
  • Cycloalkyl refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consist solely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl. Unless otherwise stated specifically in the specification, the term" cycloalkyl” is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.
  • Aryl refers to single and multiple ring radicals, including multiple ring radicals that contain separate and/or fused aryl groups.
  • Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms, such as phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical.
  • the aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, alkoxycarbonyl, etc.
  • Heterocyclyl refers to a stable 3-to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably a 4-to 8-membered ring with one or more heteroatoms, more preferably a 5-or 6-membered ring with one or more heteroatoms. It may be aromatic or not aromatic.
  • the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized ; and the heterocyclyl radical may be partially or fully saturated or aromatic.
  • heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, coumarine, morpholine; pyrrole, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.
  • “Heterocyclylalkyl” refers accordingly to a "Heterocyclyl” radical being connected via an "Alkyl” chain.
  • Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.
  • Amino refers to a radical of the formula-NH2, -NHRa or -NRaRb, optionally quaternized.
  • Halo or hal refers to halogen such as bromo, chloro, iodo or fluoro.
  • alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms ; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1
  • the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a ' C- or C- enriched carbon or 15 N-enriched nitrogen are within the scope of this invention.
  • pharmaceutically acceptable salts, solvates, prodrugs refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein.
  • non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts, prodrugs and derivatives can be carried out by methods known in the art. For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p- toluenesulphonate.
  • mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p- toluenesulphonate.
  • alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, triethanolamine, glucamine and basic aminoacids salts.
  • Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drug design and Discovery” Taylor & Francis (April 2002).
  • the compounds of the invention may be in crystalline form either as free compounds or as solvates and it is intended that both forms are within the scope of the present invention.
  • Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate.
  • the compounds of formula (I) or (IB) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I) or (IB), or of its salts, solvates or prodrugs.
  • the compounds of the present invention represented by the above described formula (I) or (IB) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds (e.g. Z, E).
  • the single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
  • the compounds of formula (I) or (IB) defined above can be obtained by available synthetic procedures similar to those described in the patent US 4,337,263 or FR 2 472 564. For example, they can be prepared by condensing a compound of Formula (II):
  • reaction of compounds of formulas (II) and (III) is preferably carried out at a temperature in the range of 60 to 120 0 C in an aprotic solvent, but not limited to, such as dimethylformamide (DMF) in the presence of an inorganic base, such as K 2 CO 3 .
  • aprotic solvent such as dimethylformamide (DMF)
  • an inorganic base such as K 2 CO 3
  • a general scheme for synthetizing compounds (II), (I) or (IB) is:
  • the intermediate compound (H) can also be prepared as described in the bibliography (see L.F.Tietze et al., Synthesis, (11), 1079-1080, 1993; F. Effenberger and W. Hartmann, Chem. Ber., 102(10), 3260-3267, 1969; both cites incorporated here by reference). It can also be prepared by conventional methods, as can be seen in the synthetic examples of the present patent application.
  • reaction products may, if desired, be purified by conventional methods, such as crystallisation and chromatography.
  • these isomers may be separated by conventional techniques such as preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • the compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms.
  • Another aspect of this invention relates to a method of treating or preventing a sigma receptor mediated disease which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • sigma mediated diseases that can be treated are diarrhoea, lipoprotein disorders, metabolic syndrome, treatment of elevated triglyceride levels, chylomicronemia, hyperlipoproteinemia; hyperlipidemia, especially mixed hyperlipidemia; hypercholesterolemia, dysbetalipoproteinemia, hypertriglyceridemia including both the sporadic and familial disorder (inherited hypertriglyceridemia), migraine, obesity, arthritis, hypertension, arrhythmia, ulcer, learning, memory and attention deficits, cognition disorders, neurodegenerative diseases, demyelinating diseases, addiction to drugs and chemical substances including cocaine, amphetamine, ethanol and nicotine, tardive diskinesia, ischemic stroke, epilepsy, stroke, depression, stress, pain, especially neuropathic
  • the term "pharmacological tool” refers to the property of compounds of the invention through which they are particularly selective ligands for Sigma receptors which implies that compound of formula I, described in this invention, can be used as a model for testing other compounds as Sigma ligands, ex. a radiactive ligands being replaced, and can also be used for modeling physiological actions related to Sigma receptors.
  • the present invention further provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.
  • compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
  • the pharmaceutical compositions are in oral form, either solid or liquid.
  • Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize starch, calcium phosphate, sorbitol or
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art.
  • the tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form.
  • Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.
  • compositions of the present invention will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.
  • Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated.
  • an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer.
  • active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
  • the compounds and compositions of this invention may be used with other drugs to provide a combination therapy.
  • the other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.
  • the following examples are given only as further illustration even if no longer part vention.
  • Step IA Synthesis of Acetic Acid N'-(3,4-Dichlorophenyl)hydrazide (V)
  • Step 3A Synthesis of 3-(2-chloroethoxy)-l-(3,4-dichlorophenyl)-5-methyl-lH- pyrazole
  • Step 4A Synthesis of 3- ⁇ l-[2-(l-(3,4-DichIorophenyl)-5-methyl-lH-pyrazol-3- yloxy)ethyl] piperidin-4-yl ⁇ -3H-imidazo [4,5-b] pyridine
  • Step IA Synthesis of Acetic Acid N'-(3,4-Dichlorophenyl)hydrazide (V)
  • Step 2A Synthesis of l-(3,4-Dichlorophenyl)-5-methyl-lH-pyrazol-3-ol (VI)
  • Step 3A Synthesis of 3-(2-chloroethoxy)-l-(3,4-dichlorophenyl)-5-methyl-lH- pyrazole
  • Step 4A Synthesis of ethyl 4- ⁇ 2-[l-(3,4-dichlorophenyl)-5-methyl-lH-pyrazol-3- yloxy] ethyl ⁇ piper azine carboxylate
  • Brain membrane preparation and binding assays for the ⁇ l -receptor were performed as described (DeHaven-Hudkins et al., 1992) with some modifications.
  • guinea pig brains were homogenized in 10 vols. (w/v) of Tris-HCl 50 mM 0.32 M sucrose, pH 7.4, with a Kinematica Polytron PT 3000 at 15000 r.p.m. for 30 s.
  • the homogenate was centrifuged at lOOOg for 10 min at 4°C and the supernatants collected and centrifuged again at 4800Og for 15 min at 4°C.
  • the pellet was resuspended in 10 volumes of Tris-HCl buffer (50 mM, pH 7.4), incubated at 37°C for 30 min, and centrifuged at 4800Og for 20 min at 4°C. Following this, the pellet was resuspended in fresh Tris-HCl buffer (50 mM, pH 7.4) and stored on ice until use.
  • Each assay tube contained 10 ⁇ L of [ 3 H](+)-pentazocine (final concentration of 0.5 nM), 900 ⁇ L of the tissue suspension to a final assay volume of 1 mL and a final tissue concentration of approximately 30 mg tissue net weight/mL.
  • Non-specific binding was defined by addition of a final concentration of 1 ⁇ M haloperidol.
  • Binding studies for ⁇ 2-receptor are performed as described (Radesca et al., 1991) with some modifications.
  • brains from sigma receptor type I ( ⁇ l) knockout mice are homogenized in a volume of 10 mL/g tissue net weight of ice-cold 10 mM Tris-HCl, pH 7.4, containing 320 mM sucrose (Tris-sucrose buffer) with a Potter-Elvehjem homogenizer (10 strokes at 500 r.p.m.)
  • the homogenates are then centrifuged at lOOOg for 10 min at 4°C, and the supernatants are saved.
  • the pellets are resuspended by vortexing in 2 mL/g ice-cold Tris-sucrose buffer and centrifuged again at lOOOg for 10 min.
  • the combined lOOOg supernatants are centrifuged at 3100Og for 15 min at 4°C.
  • the pellets are resuspended by vortexing in 3 mL/g 10 mM Tris-HCl, pH 7.4, and the suspension is kept at 25°C for 15 min.
  • the pellets are resuspended by gentle Potter Elvehjem homogenization to a volume of 1.53 mL/g in 10 mM Tris-HCl pH 7.4.
  • the assay tubes contain 10 ⁇ L of [ 3 H]-DTG (final concentration of 3 nM), 400 ⁇ L of the tissue suspension (5.3 mL/g in 50 mM Tris-HCl, pH 8.0) to a final assay volume of 0.5 mL.
  • Non-specific binding is defined by addition of a final concentration of 1 ⁇ M haloperidol.
  • All tubes are incubated at 25 0 C for 120 min before termination of the reaction by rapid filtration over Schleicher & Schuell GF 3362 glass fibre filters [previously soaked in a solution of 0,5% polyethylenimine for at least 1 h]. Filters are washed three times with 5 mL volumes of cold Tris-HCl buffer (10 mM, pH 8.0).
  • mice were first treated with the test-compound (or not in controls). Then capsaicin (1% DMSO) is injected into their paw resulting in developing pain in the effected paw. The effected paw is then treated with a mechanical stimulus and the latency time before the paw is withdrawn is measured.
  • capsaicin 1% DMSO
  • the compound according to example 6 was tested and 77% analgesia was achieved at a capsaicin concentration of 16 mg.

Abstract

La présente invention concerne des composés de formule (I) présentant une activité pharmacologique sur le récepteur sigma, des procédés de préparation de tels composés, des compositions pharmaceutiques les comprenant et l'utilisation de tels composés pour traiter ou prévenir une maladie dans laquelle est impliqué le récepteur sigma.
EP07711754A 2006-03-01 2007-03-01 Derives pyrazole utilises en tant qu'inhibiteurs du recepteur sigma Withdrawn EP1994032A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07711754A EP1994032A1 (fr) 2006-03-01 2007-03-01 Derives pyrazole utilises en tant qu'inhibiteurs du recepteur sigma

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP06004081 2006-03-01
EP06004079 2006-03-01
EP06004080A EP1829875A1 (fr) 2006-03-01 2006-03-01 Dérivés de pyrazole comme inhibiteurs de récepteur Sigma
EP07711754A EP1994032A1 (fr) 2006-03-01 2007-03-01 Derives pyrazole utilises en tant qu'inhibiteurs du recepteur sigma
PCT/EP2007/001795 WO2007098953A1 (fr) 2006-03-01 2007-03-01 Derives pyrazole utilises en tant qu'inhibiteurs du recepteur sigma

Publications (1)

Publication Number Publication Date
EP1994032A1 true EP1994032A1 (fr) 2008-11-26

Family

ID=38009379

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07711754A Withdrawn EP1994032A1 (fr) 2006-03-01 2007-03-01 Derives pyrazole utilises en tant qu'inhibiteurs du recepteur sigma

Country Status (6)

Country Link
US (2) US8202872B2 (fr)
EP (1) EP1994032A1 (fr)
JP (1) JP2009528315A (fr)
CA (1) CA2641144A1 (fr)
MX (1) MX2008011016A (fr)
WO (1) WO2007098953A1 (fr)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1829866A1 (fr) * 2006-03-02 2007-09-05 Laboratorios Del Dr. Esteve, S.A. Inhibiteurs des récepteurs sigma
EP2113501A1 (fr) * 2008-04-25 2009-11-04 Laboratorios Del. Dr. Esteve, S.A. Pyrazoles de 5-Methyl-1-(naphthalen-2-YL)-1H- utiles en tant qu'inhibiteurs de récepteur sigma
EP2112139A1 (fr) * 2008-04-25 2009-10-28 Laboratorios Del. Dr. Esteve, S.A. Procédé pour la préparation d'intermédiaires naphthalen-2-yl-pyrazol-3-one utiles dans la synthèse d'inhibiteurs de récepteur sigma
EP2116539A1 (fr) * 2008-04-25 2009-11-11 Laboratorios Del. Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy-pyrazoles en tant que ligands améliorant les effets analgésiques des opioïdes et réduisant leur dépendance
EP2292236A1 (fr) * 2009-08-14 2011-03-09 Laboratorios Del. Dr. Esteve, S.A. Ligands sigma pour la prévention ou le traitement de douleurs induites par la chimiothérapie
PT2531177T (pt) * 2010-02-04 2016-08-17 Esteve Labor Dr Polimorfos e solvatos de cloridrato de 4-[-2-[[5-metil-1-(2-naftalenil)-1h-pirazol-3-il]oxi]etil]morfolina
EP2353591A1 (fr) 2010-02-04 2011-08-10 Laboratorios Del. Dr. Esteve, S.A. Ligands sigma pour la potentialisation de l'effet analgésique d'opioïdes et d'opiacés dans la douleur post-opératoire et en atténuant la dépendance
EP2388005A1 (fr) 2010-05-21 2011-11-23 Laboratorios Del. Dr. Esteve, S.A. Ligands sigma pour la prévention et/ou le traitement du vomissement induit par la chimiothérapie ou la radiothérapie
EP2418192A1 (fr) 2010-07-30 2012-02-15 Esteve Química, S.A. Intermédiaires pour la préparation des composés 1-aryl-pyrazol-3-one utiles comme inhibiteurs de récepteur sigma
EP2415471A1 (fr) * 2010-08-03 2012-02-08 Laboratorios Del. Dr. Esteve, S.A. Utilisation de ligands sigma dans l'hyperalgie induite par opioïdes
EP2460519A1 (fr) * 2010-12-03 2012-06-06 Laboratorios Del. Dr. Esteve, S.A. Utilisation de ligands sigma pour la douleur du cancer des os
EP2460804A1 (fr) * 2010-12-03 2012-06-06 Laboratorios Del Dr. Esteve, S.A. Dérivés de 5-méthyl-1-(naphthalen-2-yl)-1h-pyrazole et leur utilisation dans la potentialisation de l'effet des analgésiques opioïdes
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
US8828995B2 (en) 2011-03-08 2014-09-09 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
EP2683700B1 (fr) 2011-03-08 2015-02-18 Sanofi Dérivés d'oxathiazine tétra-substitués, leur procédé de fabrication, leur utilisation comme médicament ainsi que médicaments en étant pourvu et leur utilisation
EP2524694A1 (fr) 2011-05-19 2012-11-21 Laboratorios Del. Dr. Esteve, S.A. Utilisation de ligands sigma dans la douleur liée au diabète de type 2
DE202011101392U1 (de) 2011-06-01 2011-10-04 Laboratorios Del Dr. Esteve S.A. Pyrazolderivate als Sigmarezeptor-Inhibitoren
EP2567959B1 (fr) 2011-09-12 2014-04-16 Sanofi Dérivés d'amide d'acide 6-(4-hydroxy-phényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
EP2818166A1 (fr) * 2013-06-26 2014-12-31 Laboratorios del Dr. Esteve S.A. Utilisation de ligands des récepteurs sigma pour la prévention et le traitement de la douleur associée à la cystite interstitielle/au syndrome de la vessie douloureuse (IC/BPS)
MA39147B1 (fr) 2013-12-17 2019-12-31 Esteve Labor Dr Combinaisons d'inhibiteurs de la recapture de sérotonine-norépinéphrine (snri) et de ligands des récepteurs sigma
DK3212637T3 (da) 2014-10-31 2021-07-12 Indivior Uk Ltd Dopamin-d3-receptorantagonistforbindelser
MA41177A (fr) * 2014-12-15 2017-10-24 Esteve Labor Dr Utilisation de ligands des récepteurs sigma dans l'arthrose
ES2700448R1 (es) * 2016-06-07 2019-02-26 Esteve Pharmaceuticals Sa Uso de ligandos del receptor sigma en la diabetes y el sindrome metabolico
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021462A1 (fr) * 2004-08-27 2006-03-02 Laboratorios Del Dr. Esteve, S.A. Inhibiteurs de récepteur sigma

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2301250A1 (fr) * 1975-02-21 1976-09-17 Bellon Labor Sa Roger Nouveaux diaryl-1, 4o-aminoalcoxy-3 pyrazoles et leurs sels
FR2460299A1 (fr) * 1979-07-05 1981-01-23 Bellon Labor Sa Roger Nouveaux derives du pyrazole et leur application therapeutique
FR2472564A1 (fr) * 1979-12-31 1981-07-03 Bellon Labor Sa Roger Nouveaux aryl-1 arylsulfonyl-4 1h-pyrazolols-3, et procede pour les preparer
GB8917069D0 (en) 1989-07-26 1989-09-13 Merck Sharp & Dohme Therapeutic agents
EP0445974A3 (en) * 1990-03-05 1992-04-29 Merck Sharp & Dohme Ltd. Spirocyclic antipsychotic agents
NZ243065A (en) * 1991-06-13 1995-07-26 Lundbeck & Co As H Piperidine derivatives and pharmaceutical compositions
WO2002102387A1 (fr) * 2001-06-18 2002-12-27 H. Lundbeck A/S Traitement de la douleur neuropathique
ATE452134T1 (de) * 2004-08-09 2010-01-15 Abbott Gmbh & Co Kg Zur behandlung von auf eine modulation des dopamin-d3-rezeptors ansprechende erkrankungen geeignete 4-piperazinylpyrimidinverbindungen

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021462A1 (fr) * 2004-08-27 2006-03-02 Laboratorios Del Dr. Esteve, S.A. Inhibiteurs de récepteur sigma

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2007098953A1 *

Also Published As

Publication number Publication date
WO2007098953A1 (fr) 2007-09-07
JP2009528315A (ja) 2009-08-06
US20090264442A1 (en) 2009-10-22
US8202872B2 (en) 2012-06-19
MX2008011016A (es) 2008-09-08
US20120232093A1 (en) 2012-09-13
CA2641144A1 (fr) 2007-09-07

Similar Documents

Publication Publication Date Title
US8202872B2 (en) Pyrazole derivatives as sigma receptor inhibitors
EP1781618B1 (fr) Inhibiteurs de recepteur sigma
US20100081659A1 (en) Sigma receptor inhibitors
US8314096B2 (en) Sigma receptor inhibitors
EP1996554B1 (fr) Inhibiteurs du recepteur sigma
EP1996580B1 (fr) Dérivés du pyrazole antagonistes des récepteurs sigma
EP2395003A1 (fr) Composés pyrazoliques en tant qu'inhibiteurs du récepteur sigma
EP1829875A1 (fr) Dérivés de pyrazole comme inhibiteurs de récepteur Sigma
EP1994008B1 (fr) Composés d'imidazole ayant une acitivité pharmaceutique vis-à-vis le recepteur sigma

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080926

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1124052

Country of ref document: HK

17Q First examination report despatched

Effective date: 20100525

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20120508

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1124052

Country of ref document: HK